Diaza-oxa-bicyclodecane derivatives and production thereof

ABSTRACT

WHEREIN R1 and R2 are linked together to form methylene, or R1 is hydrogen and R2 is methyl; and R3 is formyl, hydroxymethyl, CH(OH)-C(OH)(CH3)-CH2OH or -CH(OH)OR4 wherein R4 is hydrogen or lower alkyl group, which are useful as a medicine having antimicrobiological activities or as an intermediate for preparing compound having pharmaceutical activities against microorganisms.   Diaza-oxa-bicyclodecane derivatives of the formula:

United States Patent [191 Kamiya et al.

[ Mar. 25, 1975 DIAZA-OXA-BICYCLODECANE DERIVATIVES AND PRODUCTION THEREOF [75] Inventors: Takashi Kamiya, Suita; Shizuo Maeno, Osaka; Masahi Hashimoto, Toyonaka, all of Japan [73] Assignee: Fujisawa Pharmaceutical Co. Ltd.,

Osaka, Japan 22 Filed: Aug. 30, 1973 211 Appl. No.: 392,944

[30] Foreign Application Priority Data Sept. 8, I972 Japan 4790675 [52] US. Cl 260/2393 B, 424/244, 424/250 [51] Int. Cl. Cl2d 13/00, C07d 99/02 [58] Field of Search 260/2393 B Primary Examiner-Henry R. Jiles Assislunt Examiner-Robert T. Bond [57] ABSTRACT Diaza-oxa-bicyclodecane derivatives of the formula:

R R H 2 l /C--'C\ 0 2? H C O 2 o-- \1 NH wherein R and R are linked together to form methylene, or R, is hydrogen and R is methyl; and R is formyl, hydroxymethyl, -CH(OH)C(OH)(CH )CH- 0H or CH(Ol-l)OR wherein R is hydrogen or lower alkyl group, which are useful as a medicine having antimicrobiological activities or as an intermediate for preparing compound having pharmaceutical activities against microorganisms.

7 Claims, No Drawings DlAZA-OXA-BICYCLODECANE DERIVATIVES AND PRODUCTION THEREOF This invention relates to new diaza-oxabicyclodecane derivatives which are active against microorganisms or useful as an intermediate for preparing a pharmaceutical compound having antimicrobiological activity, and to production thereof.

Accordingly, the present invention provides, as novel compounds, diaza-oxa-bicyclodecane derivatives of the formula:

wherein R and R are linked together to form methylcne, or R is hydrogen and R is methyl; and R is formyl, hydroxymethyl,

on l l W 2 4 101211 a c 3 9 o o--c NH l H..

$2 Ho-c-cH is; Cd OH 8,]-diaza-6-hydroxy-S-methyl-l-(2-methyl-l 2, 3- trihydroxypropyl)-2-oxa-bicyclot[4,2,2]decan-7,9- dione B: 8.IO-diaza-l-formyl-6-hydroxy-5-methylene-2-oxabicy'clo[4,2,2]decan-7,9-dione CH 0H 'c': 2 b 00 H ll\lH H C CO 0( y NH CHO C: Acetals of 8,10-diaza-l-formyl-6-hydroxy-5- methylene -2-0xa-bicyclo[4,2,2]decan-7,9-dione wherein R is hydrogen or a lower alkyl group.

D: 8,10-diaza-l-hydroxymethyl-6-hydroxy-5-methyl-2- oxa-bicyclo[4,2,2]decan-7,9-dione The aforementioned four types ofcompounds can be prepared according to methods as illustrated below, respectively.

Dihydrobicyclomycin The dihydrobicyclomycin is prepared by reducing bicyclomycin and the process is illustrated in the following scheme:

(Bi'cyclomycin) Reduction I I The bicyclomycin (I) to be used as a starting compound in this reaction is known as WS-4545 substance by German Offenlegungsschrift 2150593 and can be prepared by a method as disclosed in the said publicatron.

In this reaction, the reduction is conducted by a conventional method, for example, by means of catalytic reduction, reduction with a metal and an acid [e.g. a metal such as iron, tin or zinc and acid such as an inorganic acid (hydrochloric acid, sulfuric acid or the like) or an organic acid (acetic acid or the like)]; an alloy, a metal, or its salt and water, alkaline or alcohol [e.g. an alloy, a metal or its salt such as sodium amalgam, aluminum amalgam, zinc, iron or ferrous salts and water, alkaline or alcohol such as methanol, ethanol, propanol or butanol]; a phenyl hydrazine or hydrazine; titanium chloride and hydrochloric acid, or electrolytic reduction.

As suitable examples of catalyst in the above catalytic reduction method, there may be, for example, platinum catalyst such as platinum plate, spongy platinum, platinum black, platinum colloid, platinum oxide or platinum wire; palladium catalyst such as palladium spongy, palladium black, palladium oxide, palladium on charcoal or palladium colloid; platinum group metal catalyst such as iridium, iridium colloid, ruthenium oxide, rhodium colloid or rhodium on alumina; nickel catalyst such as reduced nickel, nickel oxide or Raney nickel; cobalt catalyst such as reduced cobalt or Raney cobalt; iron catalyst such as reduced iron or Raney iron; or copper catalyst such as reduced copper, Raney copper or Ullmann copper.

The reduction is usually carried out in an inert solvent. The reaction conditions, for example, solvent to be used and reaction temperature, could be decided in accordance with the used reduction method. In general, it is preferable to employ a solvent such as water, methanol, ethanol, dimethylformamide, dimethylacetamide dioxane or the like.

The reduced compound i.e. dihydrobicyclomycin (ll), can be isolated and purified by a conventional method.

The dihydrobicyclomycin (ll), obtained by the method of this invention, is useful as medicines having antimicrobiological activities against microorganism such as Escherichia coli, Salmonella typlzosa, Shigella flexnerl, etc. and is also useful as an intermediate for preparing compound having pharmaceutical activities against microorganisms.

8, l O-diazal -formyl-6-hydroxy-S-methylene-E-oxabicyclo[4,2,2]decan-7,9-dione 8,10-diaza-l-formyl-6-hydroxy-5-methylene-Z-oxabicyclo [4,2,2]decan-7,9-dione (IV) is prepared by oxidizing bicyclomycin (l) or its mono acyl derivative. and the process is illustrated in the following scheme:

ca- '6 2 'Z co H20 H l 1 (III) o 0 NH H-C-OH HO-%- CH3 ca oa l oxidation Uh 011 l 2 2.

l I (IV) a o c0 l CHO wherein R is hydrogen or an acyl group.

The suitable example of an acyl group may be alkanoyl group having 2 to 20 carbon atoms, such as acetyl,

propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pival- The above mono-acyl ester of bicyclomycin to beused as a starting material in this reaction is known as a mono acyl ester of WS-4545 substance by German Offenlcgungsschrift 2150593 and can be prepared by a method as disclosed in the said publication.

The oxidation is carried out by a conventional method, for example, by treating bicyclomycin (l) or,

its mono acyl derivatives with a oxidizing agent such as,

periodic acid or its salt (e.g. sodium salt, potassium salt etc), lead tetraacetate or the like.

The reaction solvent to be used should be decided in accordance with the oxidizing agent used. For instance, when periodic acid or its salt is used, the reaction is carried out in an inert solvent such as water, methanol ethanol or the like. When lead tetraacetate is used, the reaction is carried out, preferably under anhydrous condition, in an inert solvent such as acetic acid, benzene, tetrahydrofuran or other organic solvent inert to this reagent.

The reaction temperature is not especially limited and the reaction is usually carried out under cooling, at room temperature or at an elevated temperature.

The object compound (IV) is isolated and purified by a conventional method.

8,lO-diaza-l-formyl-6-hydroxy-5-methylene-2-oxabicyclo [4,2,2]decan-7,9-dione (IV), obtained by the method of this invention, is useful as an intermediate for preparing compound having pharmaceutical activities against microorganisms.

Acetals of 8,10-diaza-l-formyl-6-hydroxy-5-methylene-2-oxabicyclo [4,2,2]decan-7,9-dione Acetals of 8,l0-diaza-l-formyl-6-hydroxy-5- methylene-2-oxa-bicyclo[4,2,2]decan-7,9-dione are prepared by treating 8,lO-diaza-l-formyl-6-hydroxy-5- methylene-2-oxa-bicyclo[4,2,2]decan-7,9-dione (IV) with an alkanol, and the process is illustrated in the following scheme:

The object compound is isolated and purified by a conventional method.

In a similar manner as mentioned above, hydrate of 8, l O-diazal -formyl-6-hydroxy-S-methylene-Z-oxabicyclo[4,2,2]decan-7,9-dione (V) is also prepared by treating the compound (IV) with water.

Acetals of 8, l O-diazal -formyl-6-hydroxy-5- methylene-2-oxa-bicyclo[4,2,2]deean-7,9-dione (V), obtained by the method of this invention, are useful as an intermediate for preparing compound having pharmaceutical activities against microorganisms.

8,10-diaza-l-hydroxymethyl-6-hydroxy-5-methyl-2- oxa-bicyclo[4,2,2ldecan-7,9-dione 8,10-diaza-l-hydroxymethyl-6-hydroxy-5-methyl-2- oxa-bicyclo[4,2,2]decan-7,9-dione (Vll) is prepared by reducing 8,lO-diaza-l-formyl-6-hydroxy-5- methylene-Z-oxa-bicyclol4,2,2]decan-7,9-dione (IV) or its acetals (V), and the process is illustrated in the following scheme:

wherein R is formyl or CH(OR,)OH wherein R, is hydrogen or lower alkyl group having 1 to 6 carbon atoms.

In this reaction, the reduction is conducted by a conventional method, for example, catalytic reduction, re duction with a metal and an acid [e.g. a metal such as iron, tin or zinc and acid such as an inorganic acid (hydrochloric acid, sulfuric acid or the like) or an organic acid (acetic acid or the like)]; an alloy, a metal or its salt, and water, alkaline solution or alcohol [e.g. an alloy, a metal or its salt such as sodium amalgam, aluminum amalgam, zinc, iron or ferrous salt and water, alkaline solution or alcohol such as methanol, ethanol, propanol or butanol]; titanium chloride and hydrochloric acid; or electrolytic reduction.

As suitable examples of catalyst in the above catalytic reduction method, there may be, for example, platinum catalyst such as platinum plate, spongy platinum, platinum black, platinum colloid, platinum oxide or platinum wire; palladium catalyst such as palladium spongy, palladium black, palladium oxide, palladium on charcoal or palladium colloid; platinum group metal catalyst such as iridium, iridium colloid, ruthenium oxide, rhodium colloid or rhodium on alumina; nickel catalyst such as reduced nickel, nickel oxide or Raney nickel; cobalt catalyst such as reduced cobalt or Raney cobalt; iron catalyst such as reduced iron or Raney iron; copper catalyst such as reduced copper, Raney copper or Ullmann copper.

The reduction is usually carried out in an inert solvent. The reaction conditions, for example, solvent to be used and reaction temperature should be decided in accordance with the reduction method to be used. In general, it is preferable to employ a solvent such as water, methanol, ethanol, dimethylformamide, dimethylacetoamide or dioxane.

The reduced compound can be isolated and purified by a conventional method.

8,10-diaza-l-hydroxymethyl-6-hydroxy-5-methyl-2- oxa-bicyclo[4,2,2]decan-7,9-dione (V11), obtained by the method of this invention, is useful as a intermediate for preparing compound having pharmaceutical activities against microorganisms.

The present invention is illustrated by the following examples but not limited thereto.

EXAMPLE 1 9.06 g of bicyclomycin were dissolved in 100 ml of water and the solution was shaken with 0.4 g of Pt O in hydrogenatmosphere at ambient temperature for an hour.

After the reaction was completed, the catalyst was removed by filtration and the filtrate was lyophilised. The residue was recrystallized from a methanol-ethyl ether mixture to give 6.2 g of dihydrobicyclomycin in the form of colorless prisms.

Analysis for C|2H2007N21 Calculated: C 47.36%, H 6.63%; N 9.21%.

Found C 47.21%; H 6.74% N 8.95%.

EXAMPLE 2 3.02 g of bicyclomycin were dissolved in 40 ml of water and to the solution 5.57 g of periodic acid were added, while stirring at C for 3 hours. An anion exchange resin, Amberlite 1R-45 (OH form), (Amberlite is a registered trademark) was added to thus treated solution for neutralization, and the solution was filtered and then the filtrate was washed. The filtrate was evaporated to dryness in vacuo to give 8,10-diaza- 1-formyl-6-hydroxy-5-methylene-2-oxa-bicyclo[4,2,2]decan-7,9-dione in the form of anamorphous powder. The object compound was confirmed as follows.

The methylhemiacetal obtained by treating the object compound with methanol, was physicochemically confirmed.

Yield: 0.5 g M.P.: 300C Analysis for C H O N Culcu1atcd:C 46.55%: H 5.47: N 10.86: CH O 12.02.

Found: C 46.53%: H 5.56: N 10.63: CH O 11.95. Infra-red absorption spectrum (nujol):

u,,,,,,: 3400, 3280, 1675 cm Nulear magnetic resonance spectrum (in d -DMSO solution):

T (ppm) 7.06 (multiplet, 2H)

6.70 (singlet, 3H)

6.30 (rnultiplet. 2H)

5.32 (doublet. 1H. .l=8.0 HZ) 4.95 (singlet. 1H)

4.63 (singlet, 1H)

3.49 (doublet. 1H. .l=8.0 HZ) 3.20 (singlet, 1H)

2.00 (singlet. 1H)

1.15 (singlet. lH)

2,4-Dinitr ophenyl hydrazone of 8,10-diaza-l-formyl-6- hydroxy-5-methylene-2-oxa-bicyclo[4,3,2]decan-7,9- dione:

Yellow needles M.P.: 230 231C (decomposed) EXAMPLE 3 3.4 g of monoacetate of bicyclomycin were dissolved in m1 of water and to the solution 2.75 g of periodic acid was added.

Methyl hemiacetal of 8,10-diaza-l-formyl-6- hydroxy-5-methylene-2-oxa-bicyclo[4,2,2]decan-7,9- dione was obtained by substantially the same procedures as described in Example 2. Infrared spectrum of this object compound is identical with that of the methyl hemiacetal obtained in Example 2.

EXAMPLE 4 0.3 g of the methylhemiacetal of 8,10-diaza-lformyl-6-hydroxy-5-methylene-2-oxa-bicyclo[4,2,21decan-7,9-dione were dissolved in 20 ml of methanol and the solution was shaken with 0.05 g of Pt O in hydrogen atomosphere at ambient temperature for 7.5 hours. Crude product obtained was recrystallized from a ethanol to give 0.2 g of 8,10-diaza-lhydroxymethyl-6-hydroxy-5-methyl-Z-oxa-bicyclo[4,2,2]decan-7,9-dione in the form of colorless crystals.

M.P.: 198 199C (decomposed) Mass spectrum: M* 230.09 (C H O N Infra-red spectrum (nujol):

u 3400, 3220, 3110, 1695 cm Nuclear magnetic resonance spectrum (in D 0):

wherein R and R are linked together to form methylene or R is hydrogen and R is methyl; R is formyl, hydroxymethyl, CH(OH)C(OH)(CH )CH OH, or CH(OH)OR in which R, is hydrogen or a lower alkyl group, with the proviso that when R is CH(OH)-C(OH)(CH )CH OH, R is hydrogen and R is methyl.

2. A compound according to claim 1, wherein R is hydrogen and R is methyl, and R is Cl-l(OH)-C- (OH)(CH )-CH OH.

3. A compound according to claim 1, wherein R and R are linked together to form methylene, and R is formyl.

4. A compound according to claim 1, wherein R and R are linked together to form methylene, and R is -CH(OH)OR in which R, is lower alkyl group.

5. A compound according to claim 1, wherein R and R are linked together to form methylene, and R is CH(OH)OR, in which R, is hydrogen.

6. A compound according to claim 1, wherein R is hydrogen and R is methyl, and R is hydroxymethyl.

7. A compound according to claim 4, wherein R and R are linked together to form methylene, and R is CH(OH)OR in which R, is methyl.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION 3,873, 526 March 25, 1975 Patent No. Dated lnventol-(s) Takashi Kamiya et al.

It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

on title page, inventor "Masahi Hashimoto" should read -Masashi Hashimoto--;

Column 1, line 63, "bicyclot" should read bicyclo--.

Signed and Scaled this twenty-fifth Day Of May 1976 [SEAL] Arrest:

RUTH C. MASON C. MARSHALL DANN Aflesfl'ng Office Commissioner nj'larenrs and Trademarks 

1. A COMPOUND OF THE FORMULA:
 2. A compound according to claim 1, wherein R1 is hydrogen and R2 is methyl, and R3 is -CH(OH)-C(OH)(CH3)-CH2OH.
 3. A compound according to claim 1, wherein R1and R2 are linked together to form methylene, and R3 is formyl.
 4. A compound according to claim 1, wherein R1 and R2 are linked together to form methylene, and R3 is -CH(OH)OR4 in which R4 is lower alkyl group.
 5. A compound according to claim 1, wherein R1 and R2 are linked together to form methylene, and R3 is -CH(OH)OR4 in which R4 is hydrogen.
 6. A compound according to claim 1, wherein R1 is hydrogen and R2 is methyl, and R3 is hydroxymethyl.
 7. A compound according to claim 4, wherein R1 and R2 are linked together to form methylene, and R3 is -CH(OH)OR4 in which R4 is methyl. 